A quarter of all humans exhibit dental genetic disorders in tooth number, tooth spacing, and/or tooth shape. A higher percentage develops dental defects (e.g., tooth loss, dental caries) with age. Humans replace a full dentition only once early in their lifetimes, and common strategies to replace malformed or missing teeth employ synthetic materials. There is now keen interest in tooth repair via natural mechanisms of dental stem cell renewal. Research has therefore targeted the complex process of tooth development; if we understand how nature makes and replaces teeth and dental tissues, we may better appreciate how to engineer biological tooth repair. While many specifics of tooth development have been learned using the laboratory mouse, we do not yet fully understand odontogenesis. This is because mice possess only a single (non-replacing), highly derived dentition comprised of one incisor and three molars on each jaw quadrant. The mouse incisor grows continually via a labial stem cell niche, but molars do not. Other models have not been fully developed to complement research in the mouse; birds lack teeth altogether and zebrafish have a reduced dentition in the pharynx (no oral jaw teeth). Our research focuses on the basic question of how dentitions are patterned in an evolutionary model system exhibiting extraordinary dental diversity. We study cichlid fishes from Lake Malawi (East Africa) and have used prior NIH support (R03, R21) to transform this natural assemblage of species into a powerful developmental model. Our goal is to use genetic and genomic approaches to understand the complexities of tooth development, because these data can inform biological tooth repair. This proposal has three specific aims, which will: (i) identify the molecules that pattern natural tooth replacement, (ii) fine-map a tooth shape locus to gene resolution in natural populations, and (ii) manipulate the molecular pathways found in (i) and (ii) via stage- and concentration-specific chemical treatments. We will integrate these research aims to test a model that couples tooth replacement and renewal to tooth shape via a dynamic dental stem cell niche. These aims are significant because they describe new biology discovered via a strongly integrative strategy in a new animal model of odontogenesis. PUBLIC HEALTH RELEVANCE: Accomplishing the specific aims outlined here will: identify the molecular pathways that couple tooth replacement to tooth shape (Aim 1), identify a new genetic regulator of tooth shape (Aim 2), and experimentally manipulate these pathways to modulate tooth shape and replacement (Aim 3). Knowledge of the genetic and developmental basis of cichlid tooth replacement and shape will lend general insight into vertebrate odontogenesis and dental stem cell biology, and will contribute important comparative data for studies in mouse and zebrafish. Results may identify novel therapeutic targets for human dental disorders, and new pathways for biological repair, that warrant further testing in mammalian and fish models.